The present invention is directed to solid dose nanoparticulate compositions having a synergistic combination of at least one polymeric surface stabilizer and dioctyl sodium sulfosuccinate (DOSS). The solid dose compositions exhibit superior redispersion of the nanoparticulate composition either upon administration to a mammal, such as a human or animal, or reconstitution in an aqueous electrolyte solution.
A. Background Regarding Nanoparticulate Compositions
Nanoparticulate compositions, first described in U.S. Pat. No. 5,145,684 (xe2x80x9cthe ""684 patentxe2x80x9d), are particles consisting of a poorly soluble therapeutic or diagnostic agent having adsorbed onto the surface thereof a non-crosslinked surface stabilizer. This invention is an improvement over that disclosed in the ""684 patent, as the ""684 patent does not describe the use of synergistic combinations of polymeric surface stabilizers and DOSS in solid dose compositions.
Prior U.S. patents teach the use of DOSS as a primary or secondary surface stabilizer for nanoparticulate compositions. See e.g., U.S. Pat. No. 5,145,684, for xe2x80x9cSurface Modified Drug Nanoparticles;xe2x80x9d U.S. Pat. No. 5,302,401, for xe2x80x9cMethod to Reduce Particle Size Growth During Lyophilization;xe2x80x9d U.S. Pat. No. 5,318,767, for xe2x80x9cX-Ray Contrast Compositions Useful in Medical Imaging;xe2x80x9d U.S. Pat. No. 5,336,507, for xe2x80x9cUse of Charged Phospholipids to Reduce Nanoparticle Aggregation;xe2x80x9d U.S. Pat. No. 5,346,702, for xe2x80x9cUse of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;xe2x80x9d U.S. Pat. No. 5,399,363, for xe2x80x9cSurface Modified Anticancer Nanoparticles;xe2x80x9d U.S. Pat. No. 5,401,492, for xe2x80x9cWater-Insoluble Non-Magnetic Manganese Particles as Magnetic Resonance Enhancement Agents;xe2x80x9d U.S. Pat. No. 5,429,824, for xe2x80x9cUse of Tyloxapol as a Nanoparticulate Stabilizer;xe2x80x9d U.S. Pat. No. 5,451,393, for xe2x80x9cX-Ray Contrast Compositions Useful in Medical Imaging;xe2x80x9d U.S. Pat. No. 5,466,440, for xe2x80x9cFormulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with Pharmaceutically Acceptable Clays;xe2x80x9d U.S. Pat. No. 5,470,583, for xe2x80x9cMethod of Preparing Nanoparticle Compositions Containing Charged Phospholipids to Reduce Aggregation;xe2x80x9d U.S. Pat. No. 5,494,683, for xe2x80x9cSurface Modified Anticancer Nanoparticles;xe2x80x9d U.S. Pat. No. 5,503,723, for xe2x80x9cIsolation of Ultra Small Particles;xe2x80x9d U.S. Pat. No. 5,510,118, for xe2x80x9cProcess for Preparing Therapeutic Compositions Containing Nanoparticles;xe2x80x9d U.S. Pat. No. 5,543,133, for xe2x80x9cProcess of Preparing X-Ray Contrast Compositions Containing Nanoparticles;xe2x80x9d U.S. Pat. No. 5,552,160, for xe2x80x9cSurface Modified NSAID Nanoparticles;xe2x80x9d U.S. Pat. No. 5,560,931, for xe2x80x9cFormulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;xe2x80x9d U.S. Pat. No. 5,560,932, for xe2x80x9cMicroprecipitation of Nanoparticulate Pharmaceutical Agents;xe2x80x9d U.S. Pat. No. 5,571,536, for xe2x80x9cFormulations of Compounds as Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;xe2x80x9d U.S. Pat. No. 5,580,579, for xe2x80x9cSite-Specific Adhesion Within the GI Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide) Polymers;xe2x80x9d U.S. Pat. No. 5,587,143, for xe2x80x9cButylene Oxide-Ethylene Oxide Block Copolymer Surfactants as Stabilizer Coatings for Nanoparticulate Compositions;xe2x80x9d U.S. Pat. No. 5,593,657, for xe2x80x9cNovel Barium Salt Formulations Stabilized by Non-Ionic and Anionic Stabilizers;xe2x80x9d U.S. Pat. No. 5,628,981, for xe2x80x9cImproved Formulations of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral Gastrointestinal Therapeutic Agents;xe2x80x9d U.S. Pat. No. 5,665,331, for xe2x80x9cCo-Microprecipitation of Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;xe2x80x9d U.S. Pat. No. 5,716,642, for xe2x80x9cMicroprecipitation of Nanoparticulate Pharmaceutical Agents Using Surface Active Material Derived from Similar Pharmaceutical Agents;xe2x80x9d U.S. Pat. No. 5,718,919, for xe2x80x9cNanoparticles Containing the R(xe2x88x92) Enantiomer of Ibuprofen;xe2x80x9d U.S. Pat. No. 5,747,001, for xe2x80x9cAerosols Containing Beclomethasone Nanoparticle Dispersions;xe2x80x9d U.S. Pat. No. 5,834,025, for xe2x80x9cReduction of Intravenously Administered Nanoparticulate Formulation Induced Adverse Physiological Reactions;xe2x80x9d U.S. Pat. No. 6,045,829, for xe2x80x9cNanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers;xe2x80x9d and U.S. Pat. No. 6,068,858, for xe2x80x9cMethods of Making Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface Stabilizers.xe2x80x9d In addition, several published international applications teach the usefulness of DOSS as a primary or secondary surface stabilizer for nanoparticulate compositions. See e.g., WO 98/35666, for xe2x80x9cFormulations of Nanoparticle Naproxen Tablets;xe2x80x9d WO 00/18374, for xe2x80x9cControlled Release Nanoparticulate Compositions;xe2x80x9d WO 96/25918, for xe2x80x9cAerosols Containing Nanoparticulate Dispersions;xe2x80x9d and WO 00/27363, for xe2x80x9cAerosols Comprising Nanoparticle Drugs.xe2x80x9d
Prior art patents also teach the use of DOSS as a cloud point modifier for nanoparticulate surface stabilizers. See e.g., U.S. Pat. No. 5,298,262, for xe2x80x9cUse of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization;xe2x80x9d U.S. Pat. No. 5,326,552, for xe2x80x9cNovel Formulation for Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weigh Non-ionic Surfactants;xe2x80x9d U.S. Pat. No. 5,346,702, for xe2x80x9cUse of Non-Ionic Cloud Point Modifiers to Minimize Nanoparticulate Aggregation During Sterilization;xe2x80x9d U.S. Pat. No. 5,352,459, for xe2x80x9cUse of Purified Surface Modifiers to Prevent Particle Aggregation During Sterilization;xe2x80x9d U.S. Pat. No. 5,447,710, for xe2x80x9cMethod for Making Nanoparticulate X-Ray Blood Pool Contrast Agents Using High Molecular Weight Non-Ionic Surfactants;xe2x80x9d U.S. Pat. No. 5,565,188, for xe2x80x9cPolyalkylene Block Copolymers as Surface Modifiers for Nanoparticles;xe2x80x9d U.S. Pat. No. 5,665,330, for xe2x80x9cDual Purpose Diagnostic/Therapeutic Agent Having a Tri-Iodinated Benzoyl Group Linked to a Coumarin.xe2x80x9d
And several prior art references teach the use of DOSS in nanoparticulate compositions as both a surface stabilizer and as a cloud point modifier for a primary surface stabilizer. See e.g., U.S. Pat. No. 5,466,433, for xe2x80x9cPolyiodinated Aroyloxy Esters;xe2x80x9d U.S. Pat. No. 5,472,683, for xe2x80x9cNanoparticle Mixed Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;xe2x80x9d U.S. Pat. No. 5,500,204, for xe2x80x9cNanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;xe2x80x9d U.S. Pat. No. 5,521,218, for xe2x80x9cNanoparticulate Iododipamide Derivatives for Use as X-Ray Contrast Agents;xe2x80x9d U.S. Pat. No. 5,525,328, for xe2x80x9cNanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool and Lymphatic Systems Imaging;xe2x80x9d U.S. Pat. No. 5,534,270, for xe2x80x9cMethod of Preparing X-Ray Contrast Compositions Containing Nanoparticles;xe2x80x9d U.S. Pat. No. 5,573,749, for xe2x80x9cNanoparticulate Diagnostic Mixed Carboxylic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;xe2x80x9d U.S. Pat. No. 5,573,750, for xe2x80x9cDiagnostic Imaging X-Ray Contrast Agents;xe2x80x9d U.S. Pat. No. 5,603,916, for xe2x80x9c3,5-Bis-[Alkanoyl Amino]-2,4,6-Triiodobenzyl Esters;xe2x80x9d U.S. Pat. No. 5,643,552, for xe2x80x9cNanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System Imaging;xe2x80x9d U.S. Pat. No. 5,668,196, for xe2x80x9c3-Amido-Triiodophenyl Esters as X-Ray Contrast Agents;xe2x80x9d and U.S. Pat. No. 5,670,136, for xe2x80x9c2,4,6-Triiodo-5-Substituted-Amino-Isophthalate Esters Useful as X-Ray Contrast Agents for Medical Diagnostic Imaging.xe2x80x9d
U.S. Pat. No 5,585,108, for xe2x80x9cFormulations of Oral Gastrointestinal Therapeutic Agents in Combination with Pharmaceutically Acceptable Clays,xe2x80x9d claims a nanoparticulate dispersion including, inter alia, a water-insoluble particulate drug, a surfactant which can be a polymeric stabilizer, such as hydroxypropyl methylcellulose, a pharmaceutically acceptable clay, and a secondary stabilizer, such as DOSS or sodium lauryl sulfate. See col. 7 of the patent. This reference differs from the present invention in that it is directed to a nanoparticulate dispersion, and not a solid dose nanoparticulate formulation.
U.S. Pat. No 5,298,262, for xe2x80x9cUse of Ionic Cloud Point Modifiers to Prevent Particle Aggregation During Sterilization,xe2x80x9d describes the use of DOSS in a nanoparticulate composition as an anionic surfactant useful in raising the cloud point of a surface stabilizer. According to the ""262 patent, by raising the cloud point of the surface stabilizer of a nanoparticulate composition, the composition can be heat sterilized without producing particle aggregation because of the exposure to elevated temperatures. Liquid compositions are heat sterilized, not powders. This is because sterile products are not manufactured for oral administration because of the cost, complexity, etc. Thus, this patent does not teach or suggest the use of DOSS in a solid dose formulation to increase redispersion of the nanoparticulate composition upon administration to a mammal, such as a human or animal, or reconstitution in an aqueous electrolyte solution.
Finally, U.S. Pat. No. 5,518,738, for xe2x80x9cNanoparticulate NSAID Compositions,xe2x80x9d describes a nanoparticulate solid dose of an NSAID having a film of polyvinylpyrrolidone (PVP), hygroscopic sugar, and sodium lauryl sulfate adsorbed on the surface of the drug. In the examples of this patent, solid films of the nanoparticulate composition with various redispersants are prepared, including DOSS. In contrast to the present invention, the ""738 patent teaches that a solid film of a nanoparticulate drug, DOSS, and PVP shows extremely poor redispersibility. Thus, this reference teaches away from the present invention.
Many of the prior art patents listed above also teach the usefulness of polymeric surface stabilizers for nanoparticulate compositions, such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, and polyvinylpyrrolidone.
However, the prior art does not teach or suggest the use of synergistic combinations of polymeric surface stabilizers and DOSS in solid dose compositions of nanoparticulate active agents. Nor does the prior art teach or suggest that such synergistic compositions can result in superior redispersion of the nanoparticulate composition upon administration to a mammal, such as a human or animal, or reconstitution in an aqueous electrolyte solution.
B. Background Regarding DOSS
DOSS is an anionic surfactant commercially available from a variety of sources, including Chemax Inc. (Greenville, S.C.), Finetex Inc. (Elmwood Park, N.J.), R. W. Greeff and Co. (Greenwich, Conn.), McIntyre Group Ltd. (Chicago, Ill.), Penta Mfg. Co. (Livingston, N.J.), Rhone-Poulenc Inc. Specialty Chemicals Div., (Cranbury, N.J.), RTD Chemicals Corp. (Hackettown, N.J.), Scher Chemicals Inc. (Clifton, N.J.), Spectrum Quality Products Inc. (Gardena, Calif.), Thornley Co. Inc. (Wilmington, Del.), and Van Waters and Rogers (Kirkland, Wash.). It has the chemical formula C20H37O7SNa and the following structure: 
DOSS is a widely used wetting agent and dispersant. It is a white, waxlike, plastic solid added to powdered gelatins, drink mixes, and cocoas to make them dissolve more quickly and completely in liquids. It is also used as a stabilizer in pharmaceuticals, chewing gums, and canned milks, and is added to shampoos, bath products, and skin cleansers. While the U.S. Food and Drug Administration (FDA) limits the amount of DOSS that can be used in food and drug products, it still rates the compound generally recognized as safe (GRAS). 21 C.F.R. xc2xa7 172.810.
There is a need in the art for solid dose nanoparticulate compositions exhibiting superior redispersion of the nanoparticulate composition upon administration to a mammal, such as a human or animal, or reconstitution in an aqueous electrolyte solution. The present invention satisfies this need.
The present invention is directed to the surprising and unexpected discovery that solid dose nanoparticulate compositions comprising at least one polymeric surface stabilizer and DOSS exhibit superior redispersion of the nanoparticulate composition upon administration to a mammal, such as a human or animal, or reconstitution in an aqueous electrolyte solution. The solid dose nanoparticulate compositions comprise at least one poorly soluble active agent, at least one polymeric surface stabilizer adsorbed to the surface of the active agent, and DOSS.
Another aspect of the invention is directed to pharmaceutical compositions comprising a solid dose nanoparticulate composition of the invention. The pharmaceutical composition comprises at least one poorly soluble active agent, at least one polymeric surface stabilizer adsorbed to the surface of the drug, DOSS, and a pharmaceutically acceptable carrier, as well as any desired excipients.
This invention further discloses methods of making a nanoparticulate composition having at least one polymeric surface stabilizer adsorbed on the surface of the active agent and DOSS. Such a method comprises contacting a poorly soluble nanoparticulate active agent with at least one polymeric surface stabilizer and DOSS under time and conditions sufficient to provide a nanoparticle active agent/surface stabilizer/DOSS composition. Some or all of the polymeric surface stabilizers and DOSS can be contacted with the active agent either before, during, or after size reduction of the active agent.
The present invention is further directed to methods of treatment comprising administering to a mammal in need a therapeutically effective amount of a nanoparticulate composition according to the invention.
Both the foregoing general description and the following detailed description are exemplary and explanatory and are intended to provide further explanation of the invention as claimed. Other objects, advantages, and novel features will be readily apparent to those skilled in the art from the following detailed description of the invention.